HU212943B - Process for producing piperazine derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

2,3,4,5,6,7-Hexahydro-1- &lsqbstr& 4-[1-[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylbutyryl &rsqbstr& -1H-azepin e and the pharmaceutically acceptable acid addition salts thereof are 5-HT1A binding agents useful, for example, as anxiolytics.

Description

The present invention relates to novel piperazine derivatives and to pharmaceutical compositions containing them. Compounds within the scope of this invention are agents acting on the central nervous system by virtue of their 5-HT receptor binding.

The novel compounds within the scope of the present invention are 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl] -2) of formula (A). -phenylbutyryl} -1H-azepine and its pharmaceutically acceptable acid addition salts.

British Patent Application No. 9,008,925.1 discloses compounds of formula (I) which include novel compounds of the present invention which have not been prepared and whose activity is significantly superior to the most potent compounds of said patent. The patent application discloses compounds of the formula I and their pharmaceutically acceptable acid addition salts. In the formula I, n is an integer of 1 or 2,

R is hydrogen or lower alkyl,

^R1 is aryl or nitrogen containing heteroaryl radical;

R ² is hydrogen or lower alkyl;

R ³ is aryl; C 1 -C 4 alkyl or aryl (lower alkyl>

X represents -OCOR ¹⁰ , -CO ² R ⁶ , -CONR ⁵ R ⁹ , OCO ² R ⁶ , -NR ⁴ COR ⁶ , OCONHR ¹¹ , -NHCO ₂ R ⁶ , NR ⁴ CONHR ⁶ , - CONHNHR ⁶ , -CONHOR ⁶ , (a) or (b)

R ⁴ and R ⁵ are nitrogen or lower alkyl

R ⁶ is -CHR ⁷ R ⁸ , C 3 -C 12 cycloalkyl or aryl-lower alkyl, wherein R ⁷ and R ⁸ are hydrogen or lower alkyl,

R ⁹ is hydrogen, C 1 -C 8 alkyl other than tertiary alkyl, C 3 -C 12 cycloalkyl, cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, or

8-azaspiro [4.5] deca-7,9-dione-8-yl (lower alkyl) with the proviso that when R ³ is aryl or aralkyl, R ⁹ is in the ortho position with a halogen atom, a nitro- other than phenyl substituted by thifluoroalkylcyano, sulfonic acid, sulfonamido, carboxy, carboxyalkyl, carboxyanilino, 4-carboxylaminobenzenesulfonamido and when R ⁹ is hydrogen, alkyl, aryl - either aryl (lower alkyl) R ⁵ is hydrogen or -CHR ⁷ R ⁸ , or

^R5 and ^R9 together with the nitrogen azetidino, pyrrolidino, piperidino, azepino, morpholino or piperazino ring optionally substituted lower alkyl, aryl or aryl (lower) alkyl may be substituted,

R 10 is C 3 -C 12 cycloalkyl or 2,3-dihydro [1,4] benzodioxinyl optionally substituted by lower alkyl, lower alkoxy or halogen, or when R ³ is C 4 -C 8 alkyl, R ¹⁰ may be aryl,

R ¹¹ is C 3 -C 12 cycloalkyl, aryl or aryl-lower alkyl;

R ¹² and R ¹³ are lower alkyl or C 4 -C 6 cycloalkyl together with the carbon atom to which they are attached,

R ¹⁴ is hydrogen, halogen, lower alkyl and

Y is CO or SO ₂ .

The compounds described in the above patent application may be prepared from known starting materials or starting materials obtainable by known methods. Some of these methods are described below.

X are -CONR wearer ^{five R9} groups (I) amides be prepared by that a NHR ⁵ R ⁹ (XI) with the general formula - wherein R ⁵ and R ⁹ are as defined above - a compound (III) an acid of the formula wherein n R, R ¹ , R ² and R ³ are as defined above, or an acylating derivative thereof. Acylating derivatives include acid halides, such as acid chlorides, azides, anhydrides, imidazolides (e.g., imidazolides from carbonyldiimidazole), activated esters, or O-acylcarbamide carboxamide, preferably cyclohexylcarbodiimide, obtained from a carbodiimide such as dialkylcarbodiimide, especially cyclohexylcarbodiimide . Preferably, the amine is acylated with an acid in the presence of a coupling agent such as Ι, Γ-carbonyldiimidazole, butyl chloroformate or phenylphosphinyl chloride.

An alternative method of preparing the compounds of formula (I) is by alkylating a piperazine of formula (IV) wherein R and R ¹ are as defined above with an alkylating agent capable of releasing a group of formula (V). In the formula V, n, R ² , R ³ and X are as defined above. For example, the alkylating agent may be a compound of formula VI wherein R ² , R ³ and X are as defined above. Z is a leaving group such as halogen or alkyl or arylsulfonyloxy.

The alkylating agent may also be an unsaturated compound of Formula VII, wherein R ³ and X are as defined above, by reacting the compound of Formula VII with piperazine of Formula IV by Michael reaction. The reaction is carried out at elevated temperature in the presence of an alcohol. When X is CONR ⁵ R ⁹ , a small amount of an acid catalyst can be used.

Compounds of formula (A) within the scope of the present invention may be prepared by reacting a compound of formula (VIII) wherein X is a leaving group, for example, with the anion of formula (IX). The anion can be prepared by treating the amide with a strong base such as. lithium diisopropylamide.

HU 212 943 Β

By carrying out the process described above, the compound of the invention may be obtained in the form of the free base or of an acid addition salt. When the compound of the present invention is obtained in the form of an acid addition salt, the free base can be prepared by basifying the acid addition salt solution, or, if it is a free base, the acid addition salt, in particular a pharmaceutically acceptable acid addition salt. dissolving the free base in a suitable organic solvent and treating the solution with an acid in a manner known per se.

Suitable acids for forming acid addition salts include both inorganic and organic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, boric acid, fumaric acid, malic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, para-toluenesulfonic acid, oxalic acid.

The compounds of the present invention contain an asymmetric carbon atom and may exist in various stereoisomeric forms. The compounds may be, for example, racemates or optically active. The optically active forms may be prepared by resolution of the racemates or by asymmetric synthesis. For example, resolution can be accomplished by forming the diastereomeric salts of the racemic base with an optically active acid such as dibenzoyl L-boronic acid, separating the diastereomeric salts, and converting them to the optically active base or other salts.

The compounds of the present invention are pharmaceutically active, namely, acting on the central nervous system due to their binding to 5-HT receptors. Pharmacological studies show that the compounds of the invention bind to 5-HT _1A type receptors. The compounds selectively bind more strongly to _{5-HT] A} receptor than for other types of acids, such as aj receptor. Pharmacological studies indicate that the compounds against _{5-HT] The} antagonists. The results obtained from the pharmacological examination of the compounds indicate that they are useful in the treatment of central nervous system disorders such as anxiety. They may also be used as anti-depressant agents, hypotensive agents, and in the regulation of sleep / wake cycle, nutritional behavior and / or sexual function.

The 5-HT _1A receptor binding activity of the compounds of the present invention was evaluated in rat hippocampal membrane homogenate by the method of BS Alexander and MD Wood (J. Pharm. Pharmacol., 1988, 40, 888-891).

The results show that the compounds of the invention are more potent than other compounds of formula I, including those described in 9,008,925.1. 2,3,4,5,6,7-hexahydro-1- {3- {1- [4- (2-methoxyphenyl) piperazinyl]} -2-phenyl, as described in Example 34 of British Patent Application Ser. propionyl} -1H-azepine (Compound B). Compound B is one of the most potent compounds disclosed in 9,008,925.1. British Patent Application Serial No. 4,600,198. The results are given below in which Compound C represents the isomer described in Example 2 a).

IC ₅₀ (nM) The compound 3 Compound B 9 Compound C 1

Compounds were also tested for 5HT ₎ -receptor antagonist activity in a test for 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH DPAT) antagonist syndrome in rats. The results are shown below

MED (mg / kg; s.c.) The compound 0.03 Compound B 0.3

The compounds were also tested for their potential anti-anxiety activity in a test that measures mouse exploratory activity in a two-part light / dark chamber B. Costall et al., Neuropharmacology, 1987, 26, 195-200 and JN Drawley et al., Pharmac. Biochem. 1980, 13, 167-170). The results are reported below:

MED (mg / kg; s.c.) The compound 0.03 Compound B 1

The invention also encompasses the preparation of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. These pharmaceutical compositions contain the active ingredient in admixture with a pharmaceutically acceptable carrier. Any suitable carrier known in the literature may be used in these pharmaceutical compositions. These carriers are generally in solid or liquid form or in mixtures of solid or liquid forms.

Solid pharmaceutical compositions include powders, granules, tablets, hard or soft gelatine capsules, suppositories, and the like. The solid carrier may be, for example, one or more substances which may be used simultaneously as a flavoring agent, lubricant, solubilizer, suspending agent, filler, lubricant, compression aid, binder or tablet disintegrant; the carrier may also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having a suitable compression property in suitable proportions and prepared in the shape and size desired. The powders and tablets preferably contain up to 99%, such as 0.03-99%, preferably 1-80%, of the active ingredient. Suitable solid carriers include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl

EN 212 943 Β nyl-PiTolidone, low melting point waxes and ion exchange resins.

The term "formulation" includes the formulation of an active ingredient in a capsule with an encapsulating agent such as a carrier; in this case, the active ingredient, if appropriate together with other carriers, is enclosed within the carrier. Wafers are likewise included.

Liquid formulations include solutions, suspensions, emulsions, syrups, elixirs, and the like. They are. For example, the active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof, or a pharmaceutically acceptable oil or fat. The liquid carrier may also contain other suitable additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulating agents, stabilizing agents, or osmotic pressure regulating agents. Suitable carriers for oral and parenteral administration are water, especially water containing additives such as those listed above, such as cellulose derivatives, preferably carboxymethylcellulose derivatives, preferably carboxymethylcellulose solutions; alcohols such as glycerol and glycols and derivatives thereof; oils - such as fractionated cocoa bean oil and peanut oil. For parenteral administration, the carrier may be an oily ester such as ethyl oleate and isopropyl myristate. In the case of sterile liquid preparations for parenteral administration, sterile liquid carriers are used.

Liquid pharmaceutical formulations in the form of a sterile solution or suspension may be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. When the compound is active when administered orally, it may be administered orally in liquid or solid form.

The pharmaceutical compositions are preferably formulated in unit dosage forms such as tablets or capsules. In such forms, the preparation may be subdivided into subunits containing the appropriate quantities of the active ingredient; unit dosage forms can be packaged preparations such as packaged powders, vials, ampoules, and prefilled syringes and wafers containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of tablets or capsules, packaged together. The active ingredient content of a unit dose formulation may range from 0.5 mg or less to 750 mg or more, depending on the particular need and the activity of the active ingredient.

The following examples illustrate the process of the present invention without limiting its scope to these examples.

Example 1

2,3,4,5,6,7-Hexahydro -] - (4 - [] - [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} -1H-azepine ml butyl lithium (1.5 M hexane, 7.5 mmol) was added dropwise over 5 minutes while maintaining the temperature at 8 ° C with 1.48 g (6.8 mmol) of 2,3,4,5,6,7-hexahydro- A solution of phenylacetyl-1H-azepine and diisopropylamine (1.4 g, 2.0 mL, 14 mmol) in dry toluene (16 mL) was stirred under argon for 1 hour and stirred at 0 ° C for 1 h. A solution of freshly chromatographed 1- (2-chloroethyl) -4- (2-methoxyphenyl) piperazine (73 g, 6.8 mmol) in dry toluene (4 mL) was added dropwise from 0 ° C to 20 ° C. After stirring for 18 hours at 50 ° C, water (50 ml) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml) and the combined organic layers were concentrated in vacuo to give 2.91 g of crude product as eluent. ethyl acetate to give 0.15 g of the title compound The product was dissolved in ethyl acetate (30 mL) and the solution was acidified with ethereal hydrogen chloride. The product was collected to give the title compound (0.36 g) as the hydrochloride three quarters. Melting point: 175-178 ° C.

Elemental analysis based on the formula C ₂₇ H ₃₇ N ₃ O ₂ -2HCl 10,75 H ₂ O:

Calculated: C, 62.1; H, 7.8; N, 8.5;

found: 62.05; 7.8; 7.75.

Example 2

Resolution of 2,3,4,5,6,7-Hexahydro-1- {4- (1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} -1H-azepine

a) 12.1 g of 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} - 1 H-Azepine is dissolved in ethyl acetate (30 mL) and a solution of 1 molar equivalent of dibenzoyl L-tartaric acid monohydrate in 30 mL of ethyl acetate is added. The initially formed oil was redissolved by addition of a minimal amount of acetonitrile (3.6 mL). After 3 hours, 6.2 g of crystals were obtained by filtration with an optical purity of 28% by chiral HPLC. First, recrystallization from 3: 10 ethyl acetate: acetonitrile gave 156 ml of sample having an optical purity of 84% and then crystallized again from 90 ml of methanol to give one of the enantiomers (I), dibenzoyl-L-. in the form of tartrate. Yield 2.1 g, m.p. 147150 ° C, [α] 25 D (1% in methanol).

Elemental Analysis Results a

C ₂₇ H ₃₇ N ₃ O ₂ C ₁₈ H ₄ O ₈ H ₂ O requires C, 66.6; H, 6.6; N, 5.2;

found: 66.7; 6.7; 5.1.

Optical purity 97.4%. The sample is converted to the free base of isomer I, yield 1.1 g, rotation:

[.alpha.] D @ 20 = + 53 DEG (1% in chloroform) and then converted to the hydrochloride salt in the usual manner to give a colorless powder, 0.65 g, m.p. 181-184 DEG C., rotation [α] D = +. 35 ° (1% in MeOH),

Elemental analysis for C ₂₇ H ₃₇ N ₃ O ₂ -2HC1O, 25 H ₂ O wherein:

Calculated: C, 63.2; H, 7.7; N, 8.2;

found: 63.1; 7.8; 7.9.

Optical purity 97.6%.

b) The other enantiomer (isomer II) in a similar manner

The racemate of Example 1 was formed with dibenzoyl-D-tartaric acid monohydrate. The dibenzoyl-D-tartaric acid salt of the isomer II had a melting point of 141-142 ° C, [α] 25 D = + 25 ° (1% in methanol).

Elemental Analysis Results a

C ₂₇ H ₃₇ N ₃ O ₂ Ci _g H | ₄ based O 0.25 _g H ₂ O Calcd: C 67.3%; H, 6.5; N, 5.2;

found: 67.3; 6.7; 5.2.

Rotation of the isomer II base [α] 20 D = - 26 ° (in 1% CHCl ₃ ),

The hydrochloride salt of the Π isomer has a melting point of 181-184 'C [α] D = -36' (1% in MeOH),

Analysis for C ₂₇ H ₃₇ N ₃ O ₂ -2HCl 11,75 H ₂ O:

Found: C, 60.05; H, 7.9; N, 7.8;

found: 60.2; 7.7; 7.9.

Optical purity: 98.2%.

Claims (4)

Process 1: 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} - 1H-azepine, pharmaceutically acceptable acid addition salts and enantiomers thereof, by reacting a compound of formula (VIII) wherein X is a leaving group with an anion of the amide of formula (IX) and optionally yielding the 2,3,4 5,6,7 Hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} -1H-azepine free base is converted into its pharmaceutically acceptable acid addition salt or 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] -2-phenylbutyryl} -1H-azepine the pharmaceutically acceptable acid addition salt thereof is converted into the free base and / or the resulting racemic compound is 2,3,4,5,6,7hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]]. -2-phenylbutyryl] -1H-azepine or a salt thereof. The process according to claim 1, which is 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenyl- butyryl} -1H-azepine enantiomer or a pharmaceutically acceptable salt thereof, wherein the free base is rotated at [α] d = + 53 '(in 1% CHCl ₃ ), characterized in that the appropriate starting compounds are used. The process according to claim 1, which is 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenyl- butyryl] -1H-azepine, or a pharmaceutically acceptable salt thereof, wherein the free base is rotated at [α] D = -62 ° (1% in CHCl ₃ ), characterized in that the appropriate starting compounds are used. 4. A process for the preparation of a pharmaceutical composition comprising the steps of claims 1-3. A compound of formula (A) or a pharmaceutically acceptable acid addition salt or enantiomer thereof, as defined in any one of claims 1 to 6, in admixture with excipients and / or excipients commonly used in the pharmaceutical industry to form a pharmaceutical composition.